Substituted pyridazinone compounds having various substituents have heretofore been prepared and proposed for use in a wide range of different ultimate applications. Thus, for example, U.S. Pat. Nos. 3,657,242; 3,689,652; 3,746,712; 3,812,256; 3,822,260; 3,876,786; 3,876,787; 3,931,177; and 3,975,388 disclose a variety of pharmacologically active 4,5-dihydropyridazinones. As a chemical class, those compounds comprise dihydro (saturated) ketopyridazines.
Representative of another class of related compounds are the pyridaz-3-one compounds disclosed in U.S. Pat. No. 2,839,532. The aforesaid patent is directed to 4,5-unsaturated pyridaz-3-one (or 3-ketopyridazine) compounds having a cyano, acetyl, carboxyl, carbethoxy or benzoyl group in the 4-position optionally substituted in the 5,6- positions by lower alkyl, phenyl or substituted phenyl residues. These compounds are disclosed as being useful as medicaments, particularly, analgesics, anesthetics, antibacterials or disinfectants.
U.S. Pat. No. 3,491,096 and British Pat. No. 840,522 are directed to other previously investigated pyridazone compounds. The aforementioned British patent pertains to 2-hydroxymethyl-6-phenyl-3-pyridazone and the analgesic utility thereof. U.S. Pat. No. 3,491,096 describes 2-pyridylalkylated-6-phenylpyridaz-3-one compounds possessing sedative, analgesic and antispasmodic properties, with occasional hypotensive effects being observed.
Copending Powers et al U.S. Patent Application Ser. No. 11,416, filed Feb. 12, 1979, now U.S. Pat. No. 4,238,490 and assigned to the assignee hereof, describes novel pyridazin(2H)-3-ones of the general formula ##STR1## and pharmaceutically acceptable nontoxic salts thereof wherein
R.sub.1 is hydrogen, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 carbamylmethyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 alkoxycarbonyl(C.sub.1 -C.sub.6)alkyl, C.sub.1 -C.sub.6 alkoxy(C.sub.1 -C.sub.6)alkyl; or the group ##STR2## where a is 1 to 4, inclusive, R.sub.2 is hydrogen or C.sub.1 -C.sub.4 alkyl and R.sub.3 is amino, methylthio, C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkylimino, C.sub.1 -C.sub.6 acylamino, C.sub.1 -C.sub.6 alkoxycarbonylamino, morpholinyl, piperazinyl, (C.sub.1 -C.sub.6 alkoxycarbonyl)piperazinyl, piperidinyl, pyrrolidinyl, glucuronyl or glucopyranosyl; or the group ##STR3## where R.sub.4 is hydrogen, C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, phenyl, phenyl(C.sub.1 -C.sub.6)alkyl, or R.sub.4 represents the group ##STR4## where b is 0 to 4, inclusive, R.sub.5 is hydrogen, C.sub.1 -C.sub.4 alkyl, methylthioethyl, benzyl, NH.sub.2, or benzyloxycarbamyl, and R.sub.6 is hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl or ##STR5##
R.sub.7 is acetyl, cyano, phenylsulfonyl, (C.sub.1 -C.sub.4)alkylhydrazono, naphthyl, phenyl or phenyl substituted with at least one substituent selected from the group consisting of halogen, C.sub.1 -C.sub.6 alkylamino and C.sub.1 -C.sub.4 alkoxy; and
X.sub.c and Y.sub.c are the same or different and are independently selected from the group consisting of halogen, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy where c is 0, 1 or 2;
subject to the provisos that when R.sub.7 is acetyl, phenyl or cyano, R.sub.1 is other than hydrogen; and when R.sub.7 is cyano, R.sub.1 is C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.6 carboxyalkyl or the group ##STR6## where
R.sub.4 is C.sub.1 -C.sub.6 carboxyalkyl and X.sub.c and
Y.sub.c are halo, with c being at least 1;
and the enol tautomeric derivatives and metabolites thereof. Said compounds are useful therapeutic antihypertensive agents, as described in the aforesaid U.S. Application Ser. No. 11,416, now U.S. Pat. No. 4,238,490 said application being hereby incorporated by reference in its entirety and relied upon.
As used throughout the instant specification and claims, the expressions "alkyl" and "alkoxy" are inclusive of straight and branched chain carbon-carbon linkages, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isohexyl, etc. The expression "acyl" includes, e.g., formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and the like. The term "halo" includes chlorine, fluorine, bromine and iodine. The expression "pharmaceutically acceptable nontoxic salts," as used herein, is intended to include those salts capable of being formed with the compounds of formula (I) without materially altering the chemical structure or pharmacological properties of the parent compounds. Representative of acids for reaction with sufficiently basic pyridazinone derivatives include hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, citric, etc. Alkali metal salts of carboxylic acid derivatives of formula (I) may be obtained by reaction with suitable bases, e.g., sodium hydroxide, potassium hydroxide, etc. Alkaline earth metal salts may be similarly obtained. Additionally, compounds of formula (I) containing amino acid residues, i.e., an .alpha.-amino acyl group, may be obtained as their hydrate salts such as mono- or di-hydrobromide, hydrochloride, etc., hydrate and such inorganic and organic acid addition salts of certain of the compounds of formula (I) and amino acid residues or derivatives may advantageously be employed to, for instance, alter solubility properties or augment bioavailability.
As will be apparent to those skilled in the art, the keto compounds of formula (I) wherein R.sub.1 is hydrogen may be present in the enol tautomeric form. It is also noted that certain of the R.sub.1 substituents at the 2-position, e.g., hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxyalkyl, alkylaminoalkyl, glucuronyl, etc., constitute possible enolic derivatives and/or metabolites of compounds within the scope of the present invention.
U.S. Application Ser. No. 11,416 now U.S. Pat. No. 4,238,490 teaches that the subject pyridazinones, i.e., substituted keto-pyridazine compounds of formula (I), may be prepared by various alternative methods theretofore employed in the synthesis of other pyridazinone compounds (e.g., in U.S. Pat. No. 2,839,532) or modifications thereof to obtain the R.sub.1, R.sub.7, X.sub.c or Y.sub.c substituents thereon as defined above. In general, one method for the preparation of pyridazin(2H)-3-ones comprises reacting an appropriately substituted monohydrazone, with the appropriately substituted acetic acid ester or reacting the appropriately substituted benzil and appropriately substituted hydrazide under cyclization conditions, e.g., in the presence of suitable solvents, such as xylene, acetonitrile, methanol, benzene, etc., and alkaline condensing agents, such as hydroxides, alcoholates, hydrides, alkali or alkaline earth metals, tertiary amines, etc., to effect ring closure. The foregoing general reaction scheme may be depicted as follows ##STR7## wherein R is typically an alkyl group and R.sub.7 is not here restricted by the provisos set forth earlier. As will be apparent from the foregoing description of the formula (I) substituents, the formula (Ia) products are in some instances pharmacologically active compounds of formula (I), while in other instances the formula (Ia) products are intermediates which can be converted by subsequent reactions to the compounds of formula (I).
The monohydrazone reactants may be prepared by the reaction of an appropriate substituted benzil with hydrazine hydrate. Suitable benzil starting materials may be obtained commercially or prepared by known methods, for example, cyanide ion catalyzed benzoin condensation followed by oxidation. The pyridazin(2H)-3-one compounds thus prepared may be utilized following suitable recrystallization/purification as intermediates for the preparation of further 2-substituted derivatives in accordance with the above R.sub.1 definition.
Exemplary of preferred compounds for use in the antihypertensive compositions and methods of U.S. Ser. No. 11,416 now U.S. Pat. No. 4,238,490 are compounds of the above general formula (I) wherein, correspondingly, R.sub.1 represents C.sub.1 -C.sub.4 hydroxyalkyl (especially, hydroxyethyl), esters thereof, e.g., acetate, butyrate, propanoate, formate, hemisuccinate, octadecanoate, benzoate, etc.; amino acid esters thereof corresponding to the ##STR8## group defined hereinabove wherein R.sub.4 represents ##STR9## e.g., lysine, glycine, methionine, phenylalanine, etc.; or where R.sub.1 is C.sub.1 -C.sub.4 carbamylmethyl, e.g., .alpha.-acetamido; aminoalkyl, e.g., aminomethyl, aminoethyl, etc.; C.sub.1 -C.sub.6 alkylaminoethyl, e.g., dimethylaminoethyl; glucopyranosyl; glucuronyl; 1-morpholinylethyl; 1-piperidinylethyl; 1-pyrrolidinylethyl and acetamidoethyl; and wherein R.sub.7 represents acetyl and X.sub.c and Y.sub.c are para-halo, preferably para-chloro. An especially preferred antihypertensive agent provided by U.S. Ser. No. 11,416 is 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one. According to the methods described in Ser. No. 11,416, that compound is prepared by first reacting ethanol and sodium to form sodium ethoxide, then adding ethyl acetoacetate and p,p'-dichlorobenzil monohydrazone, to afford 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one in 20% yield. That intermediate is then reacted with ethylene carbonate and potassium hydroxide in dimethylformamide to afford the desired final product. The intermediate 4-acetyl-5,6-bis(p-chlorophenyl)-2H-pyridazin-3-one can be used to prepare other antihypertensive compounds of Ser. No. 11,416 as well. See, for example, Examples 9, 10 and 11 therein. However, the poor yields heretofore obtained in the preparation of that key intermediate have been a serious problem standing in the way of commercialization of the final antihypertensive products such as 4-acetyl-5,6-bis(p-chlorophenyl)-2-(2'-hydroxyethyl)-2H-pyridazin-3-one.
In view of the foregoing, it is apparent that a serious need exists for an improved process for the preparation of the antihypertensive agents of formula (I) and intermediates thereto.